Preeclampsia (PE) is a hypertensive disorder and one of the leading causes of fetal/maternal morbidity and mortality during pregnancy. PE is characterized by impaired fetal and maternal endothelial function and excessive inflammation. Children born to PE will face increased risks of cardiovascular disorders later in life, suggesting that PE programs fetal vascular cells in utero. To date, the mechanisms underlying PE-associated fetal endothelial dysfunction remain elusive. Maternal obesity is one of the prevalent risk factors that associated with PE in developed countries. Maternal obesity increases the overall risk of PE by 3 fold. Children born to obese mother also exhibit higher blood pressure and increased risks of adverse cardiovascular outcomes in adulthood. Elevated TNF? and TGF?1 levels are associated with endothelial dysfunction in PE. Compared with lean subjects, obese women have increased pro-inflammatory cytokines (e.g. TNF?) levels in placenta and increased TGF?1 levels in maternal circulation. Human umbilical vein is the blood vessel transporting all nutrition, O2, and other humoral factors (e.g. cytokines) from the placenta and maternal system into the fetus. Hence, human umbilical vein endothelial cells (HUVECs) is widely used as a human fetal endothelial cell model. MiR192- 5p is a cardiovascular diseases-associated microRNA which regulates endothelial cell growth in cultured HUVECs. Our preliminary data have shown that increased miR192-5p expression inhibits the TNF?- and TGF?1-induced cell migration in HUVECs. We and others have reported that PE decreases miR192 expression in freshly isolated and unpassaged (P0)-HUVECs and in placentas. Our data further demonstrated that i) PE downregulated miR192-5p in male but not in female P0-HUVECs from lean pregnancies; ii) PE upregulated miR192-5p in both female and male P0-HUVECs from obese pregnancies; and iii) Male P1-HUVECs from lean PE exhibit weaker responses (monolayer integrity) to TNF? and TGF-?1 than female cells did. As TNF? and TGF?1 are both upstream regulators of miR192- 5p, these data suggest that miR192-5p plays an important and differential role in TNF? and/or TGF?1- regulated fetal endothelial function in lean and obese PE. Overall hypothesis: PE programs fetal endothelial cells by dysregulating endothelial function-associated microRNAs and their target genes, leading to fetal endothelial dysfunction, and ultimately laying the groundwork for adult onset cardiovascular disorders in children born to PE. Specifically, in this application, I will test the hypothesis that miR192-5p differentially regulates the PE-induced fetal endothelial dysfunction in lean and obese pregnancies via the TNF? and/or TGF?1 signaling pathways using HUVECs as a model. Results from our proposed studies will advance our understanding of the roles of miRNAs in PE-induced fetal sex- specific endothelial dysfunction in lean and obese pregnancies. In the long term, these studies may reveal novel biomarkers or therapeutic targets for fetal sex-specific cardiovascular risk prediction, treatment, and even prevention in children born to lean and obese PE.